Long-term outcome of 6-month maintenance chemotherapy for acute lymphoblastic leukemia in children.

In the treatment of childhood acute lymphoblastic leukemia (ALL), excess shortening of maintenance therapy resulted in high relapse rate, as shown by our previous trial, TCCSG L92-13, in which maintenance therapy was terminated at 1 year from initiation of treatment. In this study, we aimed to confirm the long-term outcome of L92-13, and to identify who can or cannot be cured by shorter duration of maintenance therapy. To obtain sentinel cytogenetics information that had been missed before, we performed genetic analysis with genomic microarray and target intron-capture sequencing from diagnostic bone marrow smear. Disease-free survival (DFS) at 10 years from the end of therapy was 66.0±2.8%. Females (n=138) had better DFS (74.6±3.7%) than males (n=142, 57.5±4.2%, P=0.002). Patients with TCF3-PBX1 (n=11) and ETV6-RUNX1 (n=16) had excellent DFS (90.9±8.7% and 93.8±6.1%, respectively), whereas high hyperdiploidy (n=23) was the most unfavorable subgroup, with 56.6±10.3% of DFS. Short duration of therapy can cure more than half of pediatric ALL, especially females, TCF3-PBX1 and ETV6-RUNX1. Our retrospective observations suggest a gender/karyotype inhomogeneity on the impact of brief therapy.

Characterization of pediatric Philadelphia-negative B-cell precursor acute lymphoblastic leukemia with kinase fusions in Japan.

Recent studies revealed that a substantial proportion of patients with high-risk B-cell precursor acute lymphoblastic leukemia (BCP-ALL) harbor fusions involving tyrosine kinase and cytokine receptors, such as ABL1, PDGFRB, JAK2 and CRLF2, which are targeted by tyrosine kinase inhibitors (TKIs). In the present study, transcriptome analysis or multiplex reverse transcriptase-PCR analysis of 373 BCP-ALL patients without recurrent genetic abnormalities identified 29 patients with kinase fusions. Clinically, male predominance (male/female: 22/7), older age at onset (mean age at onset: 8.8 years) and a high white blood cell count at diagnosis (mean: 94 200/µl) reflected the predominance of National Cancer Institute high-risk (NCI-HR) patients (NCI-standard risk/HR: 8/21). Genetic analysis identified three patients with ABL1 rearrangements, eight with PDGFRB rearrangements, two with JAK2 rearrangements, three with IgH-EPOR and one with NCOR1-LYN. Of the 14 patients with CRLF2 rearrangements, two harbored IgH-EPOR and PDGFRB rearrangements. IKZF1 deletion was present in 16 of the 22 patients. The 5-year event-free and overall survival rates were 48.6±9.7% and 73.5±8.6%, respectively. The outcome was not satisfactory without sophisticated minimal residual disease-based stratification. Furthermore, the efficacy of TKIs combined with conventional chemotherapy without allogeneic hematopoietic stem cell transplantation in this cohort should be determined.

Randomized, double-blind, placebo-controlled clinical trial of hepatocyte growth factor plasmid for critical limb ischemia.

Hepatocyte growth factor (HGF) is a potent angiogenic factor. The efficacy and safety of intramuscular injection of a naked plasmid encoding human HGF gene (beperminogene perplasmid, Collategene) was investigated in patients with critical limb ischemia (CLI) in a multicenter, randomized, double-blind, placebo-controlled trial. The randomization ratio for plasmid to placebo was 2:1. Injection sites were selected in each patient limb based on angiographic findings. Placebo or plasmid was injected on days 0 and 28. Evaluation of efficacy was carried out after 12 weeks. The primary end point was the improvement of rest pain in patients without ulcers (Rutherford 4) or the reduction of ulcer size in patients with ulcer(s) (Rutherford 5). Secondary end points were ankle-brachial pressure index, amputation, and quality of life (QOL). Forty-four patients were treated, and we performed interim analysis of efficacy in 40 patients. The overall improvement rate of the primary end point was 70.4% (19/27) in HGF group and 30.8% (4/13) in placebo group, showing a significant difference (P=0.014). In Rutherford 5 patients, HGF achieved a significantly higher improvement rate (100% [11/11]) than placebo (40% [2/5]; P=0.018). HGF plasmid also improved QOL. There were no major safety problems. HGF gene therapy is safe and effective for CLI.

The education system to master endovascular aortic repair in Japan - the Japanese Committee for Stentgraft Management.

OBJECTIVE: The Japanese Committee for Stentgraft Management (JACSM) was established with the aim of ensuring the safe and proper reach of commercial stent grafts following their regulatory approval. This study examines the validity of the practice standards developed by JACSM. METHODS: JACSM comprises 10 associations related to endovascular treatment. Based on the practice standards developed by JACSM, the status of practising institutions, practising surgeons, supervising surgeons and the results of follow-up surveys were analysed. RESULTS: In the 2.5 years following the establishment of JACSM, 298 institutions have fulfilled the practice standards. The number of practising surgeons reached 493, and the number of supervising surgeons reached 177. There were 3089 registered cases up to June 2009. The present study analysed 1570 cases registered in the 2 years from July 2006 to June 2008. The hospital mortality rate was low (0.4%) in the follow-up surveys. CONCLUSIONS: Early results following the introduction of stent grafts were generally good. The procedure spread safely without the learning curve seen in the initial stages following introduction of new medical materials, indicating that the practice standards were appropriate.

Reversal of expression of 15-lipoxygenase-1 to cyclooxygenase-2 is associated with development of colonic cancer.

AIMS: Two different pathways of linoleic acid (LA) metabolism have opposite effects on the development of colonic cancer: a protumoral prostaglandin cascade metabolized by cyclooxygenase (COX)-2, and an antitumoral peroxisome proliferator-activated receptor (PPAR)-gamma ligands metabolized by 15-lipooxygenase (LOX)-1. The aim was to examine the switching of the two LA metabolic pathways in colonic adenomas and carcinomas. MATERIALS AND METHODS: The expression of 15LOX-1 mRNA and COX-2 protein was examined in 54 adenomas, 21 pTis carcinoma-in-adenoma lesions and 36 pT3/p Stage II carcinomas of the colon by in-situ hybridization and immunohistochemistry, respectively. RESULTS: 15LOX-1 expression was found in 89% (48 of 54) of adenomas, 43% (nine of 21) of adenomas and 10% (two of 21) of carcinomas in carcinoma-in-adenoma lesions, but not in pT3 carcinomas (P < 0.0001). In contrast, COX-2 production was found in 11% (six of 54) of adenomas, 52% (11 of 21) of adenomas and 71% (15 of 21) of carcinomas in carcinoma-in-adenoma lesions, and 92% (33 of 36) of pT3 carcinomas (P < 0.0001). Concurrence of 15LOX-1 down-regulation and COX-2 up-regulation was found in 6% (three of 54) of adenomas, 33% (seven of 21) of adenomas and 71% (15 of 21) of carcinomas in carcinoma-in-adenoma lesions, and 92% (33 of 36) of pT3 carcinomas (P < 0.0001). CONCLUSIONS: These results suggest that switching of LA metabolism by reversal of the expression of 15LOX-1 and COX-2 is associated with acquisition of malignant potential in colonic neoplasia.

Effect of low-density lipoprotein apheresis on patients with peripheral arterial disease. Peripheral Arterial Disease LDL Apheresis Multicenter Study (P-LAS).

AIM: The effectiveness of low-density lipoprotein (LDL) apheresis for patients with peripheral arterial disease (PAD) was investigated to confirm a hypothesis based on subjective evidence that the amelioration of blood rheology would be the most contributing factor for improvement in clinical symptoms. Evaluation of the severity of intermittent claudication is difficult because of the lack of an accurate parameter to assess muscle ischemia during exercise, thus we objectively evaluated by non-invasive near-infrared spectroscopy (NIRS) on a treadmill in this study. METHODS: Thirty-one patients with PAD were evaluated for hemostatic function and physiological parameters such as ankle-brachial pressure index (ABI), maximum tolerated walking distance (MTWD) and recovery time (RT) or recovery ability index (RAI) on NIRS. Laboratory tests included plasma assays of total cholesterol, LDL-cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, and fibrinogen. The change in red-cell filtration rate was evaluated for the improvement of microcirculation. Statistical analysis was performed using the paired Student's t-test with Bonferroni's correction. RESULTS: A significant improvement in ABI and MTWD was observed after average 9.6+/-0.8 sessions of LDL apheresis treatment and the amelioration of microcirculation in ischemic muscle was objectively evaluated as significant improvement in RAI on NIRS. Rest pain was improved in all 5 patients with Fontaine's classification III or IV. A severe ulcer refractory to usual medications was dramatically diminished in the area by 10 sessions of LDL apheresis and fully healed 5 months after the final LDL apheresis treatment followed by medication. No angiographical change was observed in the arterial occlusive lesions in any patients. CONCLUSIONS: The effectiveness of LDL apheresis on the improvement in physiological parameters such as ABI, MTWD and clinical symptoms in patients with PAD was confirmed. The severity of intermittent claudication was objectively evaluated using non-invasive NIRS. The RT or RAI was useful parameter to evaluate the improvement in the ischemic symptoms of the extremities.

Promoter polymorphism in the macrophage migration inhibitory factor gene is associated with obesity.

OBJECTIVE: To explore the association of promoter polymorphisms of macrophage migration inhibitory factor (MIF) gene with obesity. SUBJECTS: In total, 213 nondiabetic Japanese subjects. They were divided into three groups according to World Health Organization definitions: lean (body mass index (BMI) <25 kg/m2), overweight (25 < or = BMI < 30 kg/m2) and obese (BMI> or = 30 kg/m2). METHODS: We examined two polymorphic loci in the MIF gene in the subjects: a single-nucleotide polymorphism at position -173 (G/C) and a CATT-tetranucleotide repeat polymorphism at position -794, which both can affect promoter activity in different cells. RESULTS: We detected four alleles: 5-, 6-, 7- and 8-CATT at position -794. Genotypes without the 5-CATT allele (X/X, X refers to 6-, 7- or 8-CATT alleles) were more common in obese subjects than in lean or overweight groups (P = 0.013). The X-CATT allele was more frequent in obese subjects than in lean or overweight subjects (P = 0.030). In contrast, -173G/C was not associated with obesity. Among the haplotypes of the two promoter polymorphisms, G/5-CATT ((-173G/C)/(-794[CATT](5-8))) was associated with a decreased risk of obesity (P = 0.025) and G/6-CATT with an increased risk of overweight (P=0.028). CONCLUSION: Promoter polymorphism in the MIF gene is linked with obesity.

[Endovascular stent grafting for thoracic aortic disease in elderly patients].

Despite advances in operative technique and management having improved the clinical outcomes of conventional open surgical replacement for thoracic aortic aneurysms, it remains an invasive procedure especially for aged patients. Over the past 10 years, minimally invasive endovascular surgery using a stent graft, has made significant advances for the treatment of aneurysms. For 10 years from 1995, 476 patients of thoracic aortic aneurysms were treated with the endovascular technique using the stent graft in our hospital. Exclusion of the aneurysms without endoleak were achieved within 2 weeks postoperatively in over 95%. Also in elderly patients (46/476), same good results came out. Endovascular stent grafting shows potential as a safe and useful treatment for thoracic aortic aneurysms, but further investigation should attempt to determine its efficacy over a longer postoperative period.

[Autologous fibrin sealant preparing system in coronary artery bypass grafting].

Autologous fibrin sealant (AFS) which is not based on the conventional method of co-administering fibrinogen, thrombin and aprotinin was prepared by Vivostat system, and was used in coronary artery bypass grafting (CABG). The purpose of this study was to investigate the safety and efficacy of the AFS prepared by the Vivostat system. In 6 of 68 cases of CABG, normal AFS was not prepared due to device failures. AFS was prepared and sprayed in 62 cases. There were the total of 230 anastomosis sprayed AFS and the bleeding could not seen in 225 anastomosis. Surgical hemostatic procedures (4 cases) were or other sealant usage (1 case) was performed 5 bleeding anastomosis sites. The rate of hemostasis at the anastomosis using AFS was 97.8%. This study was conducted in patients undergoing CABG. In this group of patients, a number of commercial available fibrin sealant products are routinely used. The usefulness of Vivostat as medical device to prepare and administer AFS was confirmed in this study.

[Evaluation of spinal cord ischemia in endovascular stent graft repair and surgical operation of descending thoracic or thoracoabdominal aortic aneurysms].

Between October 1996 and June 2003, endovascular stent graft repair was performed in 87 patients with descending thoracic aortic aneurysms, graft replacement was performed in 24 patients with thoracoabdominal aortic aneurysms, and endovascular stent graft repair with concomitant surgical bypass of abdominal visceral arteries was performed in 3 patients with thoracoabdominal aortic aneurysms. The retrievable stent graft was inserted and evoked spinal cord potential were monitored in order to predict spinal cord ischemia for stent graft repair. There was no paraplegia or hospital death, although 3 patients had paraparesis in stent graft repair. Two of the 3 patients with paraparesis made a full neurologic recovery. There were no cases of paraplegia or paraparesis in surgical operations with thoracoabdominal aortic aneurysm. The concomitant surgical procedure was a good technique for patients in whom cardiopulmonary bypass could not be used. Our results of stent graft repair and surgical operation for descending thoracic or thoracoabdominal aortic aneurysms were acceptable. The retrievable stent graft was useful for prediction of spinal cord ischemia before endovascular stent graft repair of descending thoracic or thoracoabdominal aortic aneurysm.

Combined minimally invasive procedure for descending thoracic aortic aneurysm with left main coronary artery disease.

A 78-year-old man had a descending thoracic aortic aneurysm with left main coronary artery disease. Combined beating heart coronary artery bypass and endovascular thoracic aortic aneurysm repair was performed without cardiopulmonary bypass. The left anterior descending artery and the obtuse marginal branch of the left circumflex artery were revascularized through a left antero-lateral small thoracotomy. The aneurysm was excluded with stent grafts through a small femoral incision. This combined less invasive procedure is a promising approach providing better surgical results in patients with thoracic aortic aneurysm and severe coronary artery disease.

Asymptomatic myocardial ischemia in relation to carotid artery stenosis among patients with aortic aneurysm.

AIM: The prevalence of asymptomatic coronary artery stenosis in relation to carotid artery stenosis is influenced by the underlying disease and has yet to be clarified. METHODS: A total of 124 consecutive Japanese patients with aortic aneurysm, but without symptoms of coronary artery stenosis, were divided into 2 groups on the basis of carotid ultrasonography: the carotid stenosis group (>or=50% luminal diameter narrowing) and the non-stenosis group. Myocardial imaging was performed using thalium-201 chloride and adenosine triphosphate disodium. RESULTS: The mean age and incidence of both cerebrovascular disease and peripheral artery disease were significantly higher in the stenosis group (n=24) than the non-stenosis group (n=100). Defining both fixed and reversible hypoperfusion as positive on the basis of myocardial imaging, a significantly higher number of positive findings were found in the stenosis group (15/24; 62.5%) than in the non-stenosis group (32/100, 32.0%), (Odds ratio: 3.54; p<0.01). The distributions of hypoperfusion defects in the stenosis group were similar to those in the non-stenosis group, but fixed hypoperfusion was more frequently seen in the stenosis group. CONCLUSION: The high prevalence of positive findings in the stenosis group indicates that carotid artery stenosis is frequently associated with coronary artery stenosis even in asymptomatic patients, and could be an indicator for advanced atherosclerosis of the coronary artery. The results confirm that stress myocardial imaging is invaluable in the detection of coronary artery stenosis, particularly in patients with carotid arteriosclerosis.

[Right atrial lipoma with calcification in ascending aorta; report of a case].

A 67-year-old male was diagnosed to have a right atrial tumor by echocardiography incidentally. Computed tomography (CT) indicated a mass which showed very low radiodensity and magnetic resonance imaging (MRI) [T1-weighted] showed the high signal intensity of tumor. We could predict the mass as lipoma. Tumor removal was performed under cardio-pulmonary bypass and under ventricular fibrillation because of the calcification in ascending aorta. Microscopically the tumor was consisted of mature adipose tissue. The postoperative course was uneventful. Cardiac lipomas are rare tumors. CT and MRI are better investigations for preoperative diagnosis. After surgical excision the prognosis is excellent.

[Surgical treatment of coronary artery-pulmonary artery fistula with coronary aneurysm].

We experienced 4 cases of coronary artery-pulmonary artery fistula with coronary aneurysm, three patients had symptoms of chest pain, and 1 patient had cardiac murmur. Coronary arteriography showed that three patients had fistulas from the left coronary artery to the pulmonary artery; and that 1 patient had a fistula from both the right and left coronary arteries to the pulmonary artery. Moreover, 1 patient had 90% diameter stenosis of segment 7. The maximum diameter of the coronary aneurysm ranged from 12 to 20 mm (average: 15.3 mm). One patient underwent closure of the opening of the fistula, 2 patients underwent multiple ligatures of fistulas, and 1 patient underwent multiple ligatures of fistulas with coronary artery bypass grafting. The postoperative course of every patient was uneventful. There have been 42 reports on this abnormality in Japan. We should treat the fistula as early as possible to prevent cardiac complications such as myocardial ischemia and rupture of coronary aneurysm.

A novel muscle LIM-only protein is generated from the paxillin gene locus in Drosophila.

Paxillin is a protein containing four LIM domains, and functions in integrin signaling. We report here that two transcripts are generated from the paxillin gene locus in Drosophila; one encodes a protein homolog of the vertebrate Paxillin (DPxn37), and the other a protein with only three LIM domains, partly encoded by its own specific exon (PDLP). At the myotendinous junctions of Drosophila embryos where integrins play important roles, both DPxn37 and PDLP are highly expressed with different patterns; DPxn37 is predominantly concentrated at the center of the junctions, whereas PDLP is highly enriched at neighboring sides of the junction centers, primarily expressed in the mesodermal myotubes. Northern blot analysis revealed that DPxn37 is ubiquitously expressed throughout the life cycle, whereas PDLP expression exhibits a biphasic pattern during development, largely concomitant with muscle generation and remodeling. Our results collectively reveal that a unique system exists in Drosophila for the generation of a novel type of LIM-only protein, highly expressed in the embryonic musculature, largely utilizing the Paxillin LIM domains.

[Survival after oozing type cardiac rupture associated with subepicardial aneurysm evaluated by echocardiography: a case report].

A 64-year-old woman was admitted to our hospital with acute myocardial infarction. She underwent emergent percutaneous transluminal coronary angioplasty. Transthoracic echocardiography revealed mild pericardial effusion on the third day. Pericarditis or cardiac rupture were suspected, so transthoracic echocardiography was repeated serially. On the sixth day, transthoracic echocardiography showed increasing pericardial effusion and abrupt interruption of the apical myocardium of the left ventricle and intact epicardial imaging with systolic expansion. The diagnosis was oozing type cardiac rupture of a subepicardial aneurysm. Surgical treatment was successful and the accuracy of the echocardiographic diagnosis was established.

[Evaluation for factors associated to early tracheal extubation after coronary artery bypass grafting].

Recent studies suggest that early tracheal extubation after coronary artery bypass grafting (CABG) may reduce intensive care unit use and cost. During recent two years, 96 patients were underwent CABG under cardiopulmonary bypass by low-dose fentanyl and isoflurane anesthesia. We compared two groups of patients for evaluation of factors associated to early tracheal extubation. 47 cases (Group A) were extubated within six hours (average 4.4 hrs) following operation, and 26 cases (Group B) were extubated later than twelve hours (average 57.5 hrs). It is suggested that emergency cases, female, elderly patients, dysfunction of kidney and long operation time associated to late extubation. But early extubation after CABG does not increase perioperative morbidity except for the cases that fell in low cardiac output syndrome or postoperative respiratory complications.

[Endoscopic thoracic sympathectomy for palmar, axillary and plantar hyperhidrosis: intermediate-term results].

From June 1996 to June 2000, 477 endoscopic thoracic sympathectomies (ETS) were performed in 242 patients with palmar hyperhidrosis. Among these, 190 patients were studied who received bilateral sympathectomy (T 2-T 3 ganglionectomy) and were followed for over six months. There were 114 females and 76 males with a mean age of 26 years. Palmar hyperhidrosis was found in all patients and axillary hyperhidrosis in 138 (73%) and plantar hyperhidrosis in 186 (98%) preoperatively. The degrees of palmar, axillary and plantar perspiration were checked immediately (1-2 weeks, 190 patients), as well as in the early (1 year, 190 patients) and late (2-4 years, 65 patients) postoperative periods. In all patients, the hands became dry or normal condition immediately after the operation, and this continued to late period. Disappearance or decrease of axillary sweating was found in 128 patients (93%) in the immediate period and 107 patients (78%) in the early period. Disappearance or decrease of plantar sweating was found in 134 patients (72%) in the immediate period and 115 patients (62%) in the early period. Among 65 patients examined in the late period, axillary hyperhidrosis was found in 24 (37%), and plantar hyperhidrosis was found in 52 (80%). Compensatory sweating was found in 80 patients (42%) in the immediate period and 137 patients (72%) in the early period. In the late period, compensatory sweating developed in 56 patients (86%). In the immediate period, 175 patients (92%) were satisfied with the results of the operation, but this decreased to 83% and 72% at early and late period. However ETS was remarkably effective for palmar or axillary hyperhidrosis and relatively effective for plantar hyperhidrosis, but development of compensatory sweating did occur in some cases.

Endovascular photodynamic therapy using mono-L-aspartyl-chlorin e6 to inhibit Intimal hyperplasia in balloon-injured rabbit arteries.

BACKGROUND AND OBJECTIVE: Intimal hyperplasia (IH) leading to restenosis is a major complication of arterial revascularization. The purpose of this study was to investigate the effect of photodynamic therapy (PDT) using mono-L-aspartyl chlorin e6 (NPe6) as a photosensitizer and intraluminal radial irradiation for inhibition of IH experimentally. STUDY DESIGN/MATERIALS AND METHODS: Study of laser transmission through the blood indicated that exclusion of blood is a prerequisite for intraluminal PDT. For homogeneous radial laser irradiation to the vessel wall, we used a newly developed cylindrical diffusing balloon laser fiber. Injuries were induced by pulling a balloon catheter through the right iliac artery of rabbits. One and 6 hours after the NPe6 injection (5mg/kg i.v.), drug distribution was examined by fluorescence microscopy. Nineteen rabbits received NPe6 at the time of injuries and PDT was performed with 664-nm laser at 30 and 10 J/cm(2) (20, 30, 40 mW/cm(2)) 1 hour after the injuries. The arteries were harvested at 2 days. In a second group of rabbits, PDT was given at 30 mW/cm(2) (30 J/cm(2)). Two weeks after treatment, the arteries were removed and examined histologically. RESULTS: NPe6 was found to be distributed selectively in the injured media. Endovascular NPe6-PDT showed complete depletion of smooth muscle cells even with 10 J/cm(2) at 2 days. IH was significantly inhibited at 14 days after PDT. CONCLUSIONS: Endovascular PDT of injured artery using NPe6 can prevent IH in this model of arterial wall injury and may become clinically useful for the prophylaxis of IH.